Increased susceptibility of brain acetylcholinesterase activity to methylmalonate in young rats with renal failure

Abstract

Tissue methylmalonic acid (MMA) accumulation is the biochemical hallmark of methylmalonic acidemia. Clinically, the disease is characterized by progressive neurological deterioration and renal failure, whose pathophysiology is still undefined. In the present study we investigated the effect of acute MMA administration on some important parameters of brain neurotransmission in cerebral cortex of rats, namely Na(+), K(+)-ATPase, ouabain-insensitive ATPases and acetylcholinesterase activities, in the presence or absence of kidney injury induced by gentamicin administration. Initially, thirty-day old Wistar rats received one intraperitoneal injection of saline or gentamicin (70 mg/kg). One hour after, the animals received three consecutive subcutaneous injections of MMA (1.67 μmol/g) or saline, with an 11 h interval between each injection. One hour after the last injection the animals were killed and the cerebral cortex isolated. MMA administration by itself was not able to modify Na(+), K(+)-ATPase, ATPases ouabain-insensitive or acetylcholinesterase activities in cerebral cortex of young rats. In rats receiving gentamicin simultaneously with MMA, it was observed an increase in the activity of acetylcholinesterase activity in cerebral cortex, without any alteration in the activity of the other studied enzymes. Therefore, it may be speculated that cholinergic imbalance may play a role in the pathogenesis of the brain damage. Furthermore, the pathophysiology of tissue damage cannot be exclusively attributed to MMA toxicity, and control of kidney function should be considered as a priority in the management of these patients, specifically during episodes of metabolic decompensation when MMA levels are higher.

Long‐term outcome of methylmalonic aciduria after kidney, liver, or combined liver‐kidney transplantation: The French experience

“…Neurological complications remain a major concern, partly related to MMlevels . All additional risk factors, such as drugs, high blood pressure, hydroelectrolytic disorders, should be strictly screened and controlled.…”

Progesterone induced neuroprotection in reperfusion promoted mitochondrial dysfunction following focal cerebral ischemia in rats

“…There was a significant elevation in AchE levels observed in tMCAO-only animals, and these were lowered with P4 administration. Studies have reported that AchE activity is increased by oxygen and nitrogen reactive species (Affonso et al, 2013). Considering that increased AchE activity has been related to progressive neurological decline and neurodegenerative diseases such as Alzheimer's and Parkinson's disease, it is presumed that a disruption in the cholinergic system may be involved in the neurological deficit associated with the tMCAO model of stroke.…”

Tbx1 haploinsufficiency causes brain metabolic and behavioral anomalies in adult mice which are corrected by vitamin B12 treatment

“…The consequences of the metabolic imbalance observed in Tbx1 +/- mice on brain health is unknown, but the presence of toxic metabolites such as MMA might affect brain function (Ribeiro et al, 2013)(Affonso et al, 2013). We therefore tested whether vB12 treatment was able to rescue the sensorimotor gating deficit (reduced pre-pulse inhibition, PPI) that we have reported (Paylor et al, 2006).…”